1. Field of the Invention
The present invention relates to prosthetic devices for use internally in a patient (hereinafter xe2x80x9cinternal prosthetic devicesxe2x80x9d), especially catheters and ports, and to compositions and methods for their flushing and coating to prevent infection and blood coagulation. In accordance with the present invention, biocidal/anti-coagulant compositions are provided for use in flushing and coating internal prosthetic devices, especially ports and catheters.
2. Description of Related Art
Hemodialysis access systems for access to a human or animal patient""s vascular system for exchange of blood between the vascular system and an external processing apparatus are well known in the art. One method comprises a catheter placed in the patient with one end extending into the central venous system and the other end affixed to one of several possible devices placed within the patient""s body that are generally referred to as xe2x80x9cports.xe2x80x9d Herein, xe2x80x9cvesselxe2x80x9d is defined as any conduit carrying a fluid within the patient""s body. These devices generally comprise a chamber having an access opening sealed by means of a septum and having an egress from a second location leading to the catheter that is disposed within a fluid space or vessel. The septum allows a needle to pass into the chamber, but then closes when the needle is removed, thereby preventing leakage from within the space or vessel and also preventing anything from entering or exiting the chamber. These devices are usually implanted below the skin to prevent infection, other contamination, and mishandling.
Recently, an improved device of this class has been developed and described in U.S. Pat. No. 5,954,691 and U.S. patent application Ser. No. 09/083,078, filed May 21, 1998. These inventions are directed to a hemodialysis access system for access to a human or animal patient""s vascular system for high fluid flow rate exchange of blood between the vascular system and an external processing apparatus at a volumetric flow rate in excess of 250 mL/minute, and comprising, in combination,
(a) a needle assembly comprising a lumen defined by an interior surface and constructed and arranged for puncturing the skin of the patient and for carrying blood therethrough at a flow rate consistent with the high blood flow requirement of the blood exchange process;
(b) a subcutaneously implantable access device permitting fluid connection to a vessel or space within a patient""s body, the device comprising
(i) a channel structure providing a flowpath having a straight or gently changing flow direction and having an interior surface and a distal end and a proximal end with reference to the patient""s skin puncture site and constructed and arranged for insertion of the needle through the proximal end of the channel and withdrawal of the needle therefrom,
(ii) a seal arranged within the channel and movable between first and second positions, where the seal, in the first position, with the needle not inserted through the seal, prevents fluids from passing the seal and, in the second position, with the needle inserted through the seal, allows fluids to pass through the needle and emerge substantially at the channel distal end, and where blood flowpath transitions between the needle interior surface and the channel interior surface are substantially continuous and smooth when the means for sealing is in the second position; and
the device further comprising structure for joining the channel distal end to a catheter that extends to an internal vessel of the patient""s body, and wherein such joining is continuous and smooth along the interior surfaces of the channel and catheter.
As with any invasive procedure, prevention of infection has been a problem, particularly with a device that must remain in place over protracted periods of time. Coagulation of the blood in and around the catheter and/or port has also proven troublesome and methods are needed for its prevention, particularly with regard to inhibiting the clogging of the catheter, which can diminish or destroy its usefulness. A significant amount of research has been directed to the alleviation of these problems.
It is standard procedure to flush catheters and/or ports with an anticoagulant, such as heparin. However, heparin is not an antibacterial and, in addition, if not carefully controlled, it can carry the anti-coagulation process too far, thereby presenting a risk of hemorrhage. It is also known in the art to employ an antibiotic along with the anticoagulant, but if this is done, as is always the case with the use of antibiotics, the probability increases that hybrid microorganisms will be produced having immunity to the applied antibiotic. For this reason, it is desirable in the medical arts to minimize the use of antibiotics to as great an extent as possible in order to conserve their efficacy over a prolonged period.
U.S. Pat. No. 4,107,305 discloses a method of combating endotoxaemia by administering an effective amount of a taurolin composition.
U.S. Pat. No. 4,445,889 discloses a method for preventing an infection in a patient introduced through a indwelling catheter, the method comprising, connecting the patient to the catheter, connecting the catheter to a fluid receiving container, admitting into the container a biocidal dispensing device, and releasing a biocide into fluid in the container for inhibiting the growth of infectious bacteria in the container and concomitantly their introduction into the catheter and the patient.
U.S. Pat. No. 4,587,268 discloses a composition for the treatment of wounds comprising a resorbable aqueous gel having dissolved or dispersed therein one or more water-soluble medicaments, which are preferably an antibiotic or a methylol transfer antibacterial.
U.S. Pat. No. 4,626,536 discloses the use of taurolin compounds to combat toxic proteins or peptides, e.g., venoms, fungal toxins and bacterial exotoxins, in the bloodstream of humans or warm-blooded animals.
U.S. Pat. No. 4,797,282 discloses a drug depot, which can be implanted in the body, for the controlled, delayed release of cytostatics, comprising a synthetic material based on polyacrylates and/or polymethacrylates containing a cytostatic and at least one amino acid.
U.S. Pat. No. 4,853,225 discloses an implantable medicament depot useful for combating infections comprising physiologically acceptable excipients and at least one delayed release active compound that is a chemotherapeutic of the gyrase inhibitor type.
U.S. Pat. No. 4,960,415 discloses a device for inserting in wounds and wound cavities consisting of a container containing a pharmaceutically active substance, the walls of this container consisting at least partly of a membrane, preferably a semi-permeable membrane, which allows the active substance to escape into the wound area. The container is, more preferably, a dialysis tube. In order to drain off wound secretions, the container containing the pharmaceutically active substance, particularly taurolidine, is conveniently connected to a drainage tube. Preferably, a drainage tube is used in which the end that leads into the wound is split into filaments.
U.S. Pat. No. 5,077,281 discloses the use of taurolin compounds as blood coagulation-inhibiting agents and as abacterial inflammation-inhibiting agents. According to the patent, taurolin has outstanding coagulation-inhibiting action and is especially suitable for use in medical conditions requiring dialysis and for vascular prostheses. It is also disclosed that these compounds can be used together with other anti-coagulants such as coumarin or heparin.
U.S. Pat. No. 5,093,117 discloses pharmaceutical compositions that are said to be useful for the treatment or prophylaxis of Gram-negative bacteremia or septic shock. These compositions contain a bactericidal effective amount of polyclonal immunoglobulins against Gram-negative bacteria and a blood clot-dissolving effective amount of protein C. The compositions may further contain one or more protein C cofactors and monoclonal antibodies against Gram-negative bacterial endotoxins. A method for the treatment or prophylaxis of Gram-negative bacteremia or septic shock comprises administering, either together or separately, a bactericidal effective amount of polyclonal immunoglobulins agains Gram-negative bacteria and a blood clot-dissolving effective amount of protein C. The method may optionally include administering one or more protein C cofactors and monoclonal antibodies against Gram-negative endotoxins.
U.S. Pat. No. 5,210,083 discloses an aqueous solution containing a bacterially effective concentration of taurolidine and/or taurultam together with a parenterally acceptable polyol. The aqueous solution is said to be particularly suitable for parenteral administration.
U.S. Pat. No. 5,362,754 discloses pharmaceutical compositions of a mixture of minocycline and EDTA (M-EDTA) and methods of using the compositions in maintaining the patency of a catheter port. Methods for inhibiting the formation of polysaccharide-rich glycocalyx (such as the glycocalyx of staphylococcal organisms) are also provided using an M-EDTA solution. The M-EDTA solution may also be used to pretreat a medical device to prevent adherence of infectious organisms, such as S. epidermis and S. aureus. The compositions destroy and prevent the formation of polysaccharide-rich glycocalyx.
U.S. Pat. No. 5,545,213 discloses articles having a graft polymer with a net ionic charge bonded to a polymeric substrate surface to provide an improved method for administering a bioactive agent having a net ionic charge. The articles are said to be especially useful as thromboresistant and or antimicrobial medical devices.
U.S. Pat. No. 5,593,665 discloses products containing tumor necrosis factor and taurolidine and/or taurultam as a combined preparation for simultaneous, separate or sequential use for treatment of patients suffering from medical conditions mediated by tumor necrosis factor.
U.S. Pat. No. 5,688,516 discloses compositions and methods of employing compositions in flushing and coating medical devices. The compositions include selected combinations of a chelating agent, anticoagulant, or antithrombotic agent, with a non-glycopeptide antimicrobial agent, such as the tetracycline antibiotics. Methods for using these compositions for coating a medical device and for inhibiting catheter infection are also disclosed. Particular combinations include minocycline or other non-glycopeptide antimicrobial agent together with EDTA, EGTA, DTPA, TTH, heparin and/or hirudin in a pharmaceutically acceptable diluent.
U.S. Pat. No. 5,718,899 discloses compositions containing a high concentration of the full repertoire of immunoglobulins that are used to combat infections from microorganisms and viruses at a wound, surgical, or burn site, or normal tissue at times of risk of infection. The compositions are applied directly to a wound or burn site as an ointment, creme, fluid, spray, or the like, prior to vital or bacterial attachment or biofilm formation such that adhesion of the pathogens is inhibited and the pathogens closest to the wound or burn site will be pre-opsonized for phagocytic killing prior to toxin release. The immunoglobulins in the composition can be immobilized on a biocompatible material such as collagen, fibrin, hyaluronan, biodegradable polymers, and fragments thereof, which will be placed in situ at the wound, surgical, or burn site. In addition, the immunoglobulins in the composition may be coated on the body contacting surface of an implantable device such as a catheter, contact lens or total joint. The compositions are said to have particular application in preventing infections.
U.S. Pat. No. 5,752,941 discloses central venous polyurethane catheters having a thin hydrophilic coating loaded with an antibiotic of the ramoplanin or any mixture thereof and their use in preventing catheter related infections. These catheters are said to be useful to prevent bacterial adherence and colonization and, therefore, to lower risk of vascular infections in catheterized patients. The method of preparing the catheter of the invention consists in incubating polyurethane catheters coated with a hydrophilic film in an aqueous solution of the selected antibiotic.
U.S. Pat. No. 5,783,570 discloses an organic solvent-soluble mucopolysaccharide consisting of an ionic complex of at least one mucopolysaccharide (preferably heparin or heparin derivative) and a quaternary phosphonium, an antibacterial antithrombogenic composition comprising said organic solvent-soluble mucopolysaccharide and an antibacterial agent (preferably an inorganic antibacterial agent such as silver zeolite), and to a medical material comprising said organic solvent soluble mucopolysaccharide. The organic solvent-soluble mucopolysaccharide, and the antibacterial antithrombogenic composition and medical material containing same are said to easily impart antithrombogenicity and antibacterial property to a polymer to be a base material, which properties are maintained not only immediately after preparation of the material but also after long-term elution.
U.S. Pat. No. 5,788,979 discloses a method for coating a biomaterial to be placed in contact with a patient""s blood flow to inhibit blood coagulation from adhering to the biomaterial that would otherwise result from such contact. A biodegradable material of liquid state compatible with the blood and tissue of the human body is prepared, and an anti-coagulant drug is incorporated into the liquid state of the biodegradable material to form a liquid coating material. The liquid coating material is adhesively applied to a surface of the biomaterial in a substantially continuous overlying layer having a formulation, pattern and thickness selected according to the period of time over which the coating material is to perform its anti-coagulant action. Thereafter the coating material is dried to a layer thickness less than about 100 microns for continuous disintegration thereof as a function of time when the layer is in contact with flowing blood.
Gorman et al., J. Clin. Pharm. Ther. 12:393-399 (1987) reported the examination of three antimicrobial agents, taurolidine, chlorhexidine, and povidone-iodine for microbial anti-adherence activity. Two adherence systems were investigated: an oral isolate of Candida albicans to human buccal epithelial cells and a urine isolate of E. coli to human uroepithelial cells. Each of the three agents exhibited significant anti-adherence activity, which was concentration dependent.
Root et al., Antimicrobial Agents and Chemotherapy 32(11):1627-1631 (1988) reported that granulocytopenic patients with an intravascular catheter are at increased risk for infection with S. epidermis. During the intervals when the catheters are not being used for infusions, it is customary to maintain patency of the catheter lumen with a solution containing heparin. The authors showed that heparin does not inhibit the growth of S. epidermis isolated from the catheter of an infected patient. A 20-mg/mL solution of disodium EDTA, a chelating agent that effectively anticoagulates blood at this concentration, was shown to be bactericidal for an initial inoculum of 103 CFU of staphylococci per mL in 24 hours. Vancomycin, an antibiotic that is often employed to treat Staphylococcus infections was also found to be bactericidal for initial inocula of 103 CFU/mL at doses of 6.7 xcexcg/mL, a drug concentration in the therapeutic range. The authors recommended that EDTA be studied as a replacement for heparin solutions for the maintenance of intravenous catheters in granulocytopenic patients, in view of its low cost, effectiveness as an anticoagulant, and bactericidal activity.
Jones et al., J. Appl. Bacteriol. 71:218-227 (1991) examined the effects of three non-antibiotic, antimicrobial agentsxe2x80x94taurolidine, chlorhexidine acetate, and povidone-iodinexe2x80x94on the surface hydrophobicity of the clinical strains E. coli, S. saprophyticus, S. epidermidis, and C. albicans. At concentrations reported to interfere with microbial-epithelial cell adherence, all three agents were found to alter the cell surface hydrophobicity. However, these effects failed to exhibit a uniform relationship. Generally, taurolidine and povidone-iodine treatments decreased the hydrophobicity of the strains examined, whereas chlorhexidine acetate effects depended upon the micro-organism treated.
Traub et al., Chemotherapy 39:322-330 (1993) examined taurolidine for bactericidal activity against a representative number of multiple-antibiotic-resistant bacterial isolates in broth as well as in the presence of bovine and human serum and fresh defibrinated human blood. The authors suggested that this antimicrobial substance might be employed for topical treatment of patients colonized or superficially infected by glycopeptide-resistant strains of E. faecium, S. aureus (GRMRSA), or by Enterobacteriaceae producing wide-spectrum xcex2-lactamases.
Willatts et al., Crit. Care Med. 23(6): 1033-1039 (1995) reported that taurolidine had no beneficial therapeutic effect on the outcome of patients admitted to the intensive therapy unit of a university teaching hospital with sepsis syndrome, using clinical, bacteriologic outcomes, progression of endotoxemia, resolution of organ failure, and 28-day mortality rate as end points.
Darouiche et al., Nutrition 13(4)(suppl):26S-29S (1997) reported that the prevention of vascular catheter-related infection mostly centers around inhibiting the adherence to the catheter of microorganisms originating from either the skin or the catheter hub. They described two general approaches that can be used non-exclusively for the successful prevention of vascular catheter-related infection. The first approach does not use antimicrobial agents and includes measures such as placement and maintenance of vascular catheters by a skilled infusion therapy team and use of maximal sterile barriers. The second approach uses antimicrobial agents and involves the application of topical disinfectants such as chlorhexidine, use of silver-impregnated subcutaneous cuffs (for short-term central venous catheters), flushing catheters with a combination of antimicrobial and antithrombic agents, and coating of catheters with either antiseptic (chlorhexidine and silver sulfadiazine) or antimicrobial agents (minocycline and rifampin).
In a talk presented at the 30th annual meeting of the American Society of Nephrology, held Nov. 2-5, 1997 in San Antonio, Tex., Sodemann et al. reported on a four year trial of a gentamicin/sodium citrate mixture as an antibiotic-lock technique for salvage and prevention of catheter-related infections. They concluded that the replacement of catheters due to infection can be avoided by routine application of the concentrated gentamicin/citrate mixture and that even the salvage of intraluminally contaminated catheters is possible.
The disclosures of the foregoing are incorporated herein by reference in their entirety.
Notwithstanding the above-described contributions to the art, a need continues to exist for a safe and effective method for the prevention of infection and blood coagulation in patients whose illness requires the implantation of internal prosthetic devices, e.g., catheters and ports.
In accordance with the present invention, biocidal/anti-coagulant compositions are provided for use in flushing and coating internal prosthetic devices, especially catheters and ports.
The present invention is directed to an internal prosthetic device comprising:
(a) means for providing a continuous flowpath, crossing a patient""s skin, between an external-to-patient site and an internal-to-patient site;
(b) means for blocking the flowpath; and
(c) a biocidal lock comprising:
(i) an anticoagulant; and
(ii) a non-antibiotic biocide.
More particularly, the present invention is directed to an internal prosthetic device access system comprising:
(a) means for providing a continuous flowpath, crossing a patient""s skin, between an external-to-patient site and an internal-to-patient site;
(b) means for blocking the flowpath at a point under the patient""s skin;
(c) means for removing the flowpath portion crossing the patient""s skin; and
(d) a biocidal lock comprising:
(i) an anticoagulant; and
(ii) a non-antibiotic biocide.
In a particularly preferred embodiment, the present invention is directed to a hemodialysis access system comprising:
(a) means for providing a continuous flowpath, crossing a patient""s skin, between and external-to-patient dialysis site and an internal blood vessel of the patient, the means including a flow conduit having no more than gentle changes in direction and whose internal surfaces are smooth and free of abrupt changes in flow area and define a flowpath sized for hemodialysis flow rates, and free of obstructions to provide low flow resistance and avoid any stagnation point;
(b) means for blocking the flowpath at a point under the patient""s skin;
(c) means for removing the flowpath portion crossing the patient""s skin; and
(d) a biocidal lock comprising:
(i) an anticoagulant; and
(ii) a non-antibiotic biocide.
In another preferred embodiment, the present invention is directed to a hemodialysis access system for access for a human or animal patient""s vascular system for high fluid flow rate exchange of blood between the vascular system and an external processing apparatus at a volumetric flow rate in excess of 100 mL/minute and having a decreased proclivity for effecting infection and blood coagulation, and comprising, in combination,
(a) a needle assembly comprising a lumen defined by an interior surface and constructed and arranged for puncturing the skin of the patient and for carrying blood therethrough at a flow rate consistent with the high blood flow requirement of the blood exchange process;
(b) a subcutaneously implantable access device permitting fluid connection to a vessel or space within a patient""s body, the device comprising:
(i) a channel structure providing a flowpath having a straight or gently changing flow direction and having an interior surface and a distal end and a proximal end with reference to the patient""s skin puncture site and constructed and arranged for insertion of the needle through the proximal end of the channel and withdrawal of the needle therefrom,
(ii) a seal arranged within the channel and movable between first and second positions, where the seal, in the first position, with the needle not inserted through the seal, prevents fluids from passing the seal and, in the second position, with the needle inserted through the seal, allows fluids to pass through the needle and emerge substantially at the channel distal end, and where blood flowpath transitions between the needle interior surface and the channel interior surface are substantially continuous and smooth when the means for sealing is in the second position; and
the device further comprising structure for joining the channel distal end to a catheter that extends to an internal vessel of the patient""s body, and wherein such joining is continuous and smooth along the interior surfaces of the channel and catheter; and
(c) a biocidal lock comprising:
(i) an anticoagulant; and
(ii) a non-antibiotic biocide.
In a particularly preferred embodiment, the access system further comprises a catheter constructed and arranged for implantation between the device at a proximal catheter end and to or into a patient""s blood vessel at a distal catheter end and means for attaching the catheter to the surrounding patient tissue.